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Publication numberUS5232921 A
Publication typeGrant
Application numberUS 07/632,609
Publication dateAug 3, 1993
Filing dateDec 27, 1990
Priority dateMar 12, 1987
Fee statusLapsed
Also published asUS5378706
Publication number07632609, 632609, US 5232921 A, US 5232921A, US-A-5232921, US5232921 A, US5232921A
InventorsKathleen Biziere, Dominique Olliero, Paul Worms
Original AssigneeSanofi
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Thiazole derivatives active on the cholinergic system, process for obtention and pharmaceutical compositions
US 5232921 A
Abstract
The invention relates to thiazole derivatives corresponding to the general formula: ##STR1## in which: R1 and R2 each independently represent hydrogen; a C1 -C4 alkyl group; a phenyl group or a phenyl group monosubstituted or polysubstituted by a halogen atom, a C1 -C4 alkyl group, a C1 -C4 alkoxy, nitro or hydroxyl group; or one of the groups R1 and R2 denotes hydrogen and the other represents a naphthyl group; a benzyl group; an α,α-dimethyl-benzyl group; a cyclohexyl group; a biphenyl group; a thienyl group of an adamantyl group; or alternatively R1 and R2, taken together, represent a group; ##STR2## in which the phenyl group is bonded to the 4-position of the thiazole and the group (CH2)m to the 5-position, m represents an integer equal to 2 or 3 and R5 denotes hydrogen or a nitro group, R3 is H or an alkyl group and R4 is notably an alkyl substituted by an amino group, a pyrrolidino, or a pyridino group.
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Claims(14)
What is claimed is:
1. An aminothiazole derivative having the formula: ##STR258## wherein: R1 and R2 each independently represent H; C1 -C4 alkyl; unsubstituted phenyl or phenyl monosubstituted or polysubstituted by halogen, C1 -C4 alkyl, C1 -C4 alkoxy, nitro or hydroxyl; or one of R1 and R2 denotes H and the other represents naphthyl; benzyl; α,α-dimethylbenzyl; cyclohexyl; biphenyl; or adamantyl; with the proviso that if one of the groups R1 and R2 denotes H, the other is different from H or methyl;
R3 represents H or C1 -C4 lower alkyl; and
R4 represents:
a group ##STR259## in which A1 denotes linear or branched C2 -C5 alkyl, and R6 and R7, taken independently, represent H, C1 -C4 alkyl or C3 -C6 cycloalkyl, or alternatively R6 and R7, taken with the nitrogen atom to which they are bonded, form a pharmaceutically-acceptable 5-membered or 6-membered heterocycle containing one or two nitrogen atoms as ring members or a nitrogen atom and an oxygen atom as ring members, with the proviso that, if R1 and R2 are both CH3, and R3 is H, and A1 is linear C2 alkyl, then R6 and R7 exclude C1-3 -alkyl;
a group: ##STR260## in which A2 denotes a group (CH2)m, where m=0, 1, 2 or 3, which is bonded to the pyridine ring in the 2-, 3- or 4-position;
a group: ##STR261## in which A2 is as indicated above; or a group: ##STR262## in which R8 denotes C1 -C4 alkyl; or alternatively the substituent ##STR263## represents a group: ##STR264## in which R8 is as indicated above, with the proviso that when R1 is H or C1 -C4 alkyl, R2 is not C1 -C4 alkyl or cyclohexyl; or an addition salt thereof with a pharmaceutically acceptable mineral or organic acid.
2. An aminothiazole derivative as claimed in claim 1, wherein R4 represents a group: ##STR265## in which A1 denotes a linear or branched C2 -C5 alkyl group and R6 and R7, taken independently, represent hydrogen, a C1 -C4 alkyl group or a C3 -C6 cycloalkyl group, or alternatively R6 and R7, taken with the nitrogen atom to which they are bonded, form a pharmaceutically-acceptable 5-membered or 6-membered heterocycle containing one or two nitrogen atoms as ring members or a nitrogen atom and an oxygen atom as ring members, with the proviso that, if R1 and R2 are both CH3, and R3 is H, and A1 is linear C2 alkyl, then R6 and R7 exclude C1-3 -alkyl.
3. An aminothiazole derivative as claimed in claim 1 in which R4 represents a group: ##STR266## in which A2 denotes a group (CH2)m, where m=0, 1, 2 or 3, which substitutes the pyridine ring in the 2-, 3- or 4-position.
4. An aminothiazole derivative as claimed in claim 1 in which R4 represents a group: ##STR267## in which A2 is an defined above.
5. An aminothiazole derivative as claimed in claim 1 in which R1 and R2 each independently denote hydrogen; a C1 -C4 alkyl group; a phenyl group or a phenyl group monosubstituted or polysubstituted by a halogen atom, a C1 -C4 alkyl group, a nitro group or a hydroxyl group; or one of the groups R1 and R2 denotes hydrogen and the other represents a naphthyl group; a benzyl group; an α,α-dimethylbenzyl group; a cyclohexyl group; a biphenyl group or an adamantyl group, with the proviso that if one of the groups R1 or R2 denotes hydrogen, the other is different from H or methyl.
6. An aminothiazole derivative having the formula: ##STR268## wherein: R1 and R2 each independently represent hydrogen; a C1 -C4 alkyl group; a phenyl group or a phenyl group monosubstituted or polysubstituted by a halogen atom, a C1 -C4 alkyl group, a C1 -C4 alkoxy group, a nitro group or a hydroxyl group; or one of the groups R1 and R2 denotes hydrogen and the other represents a naphthyl group; a benzyl group; an α,α-dimethyl-benzyl group; a cyclohexyl group; a biphenyl group; and
R4 represents;
a group: ##STR269## in which A1 denotes a linear or branched C2 -C5 alkyl group; and R6 and R7 each independently represent hydrogen or a C1 -C4 alkyl group; R1 is hydrogen; and R2 is an unsubstituted or substituted phenyl group.
7. An aminothiazole derivative as claimed in claim 6, wherein R2 is an unsubstituted phenyl group; A1 is (CH2)3 ; and R6 and R7 are each CH3.
8. A compound as claimed in claim 7, wherein R3 is hydrogen.
9. An aminothiazole derivative as claimed in claim 1, wherein said halogen substituted on the phenyl substituent R1 or R2 is chlorine or fluorine.
10. An aminothiazole derivative as claimed in claim 1, wherein said C1 -C4 alkyl substituted on the phenyl substituent R1 or R2 is a methyl group.
11. An aminothiazole derivative as claimed in claim 2, wherein R6 and R7, taken with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine or N-alkyl-piperazine ring.
12. A pharmaceutical composition comprising an amount, effective for stimulating cholinergic transmission in a person suffering from memory disorder or senile dementia, of an aminothiazole derivative according to claim 1 and a pharmaceutically acceptable vehicle.
13. A pharmaceutical composition as claimed in claim 12, wherein said amount of aminothiazole derivative is from 20 to 500 mg.
14. A method of treating a patient suffering from a memory disorder or senile dementia, comprising administering to said patient in need of such treatment an amount effective for stimulating cholinergic transmission of an aminothiazole derivative having the formula: ##STR270## wherein: R1 and R2 each independently represent H; C1 -C4 alkyl; unsubstituted phenyl or phenyl monosubstituted or polysubstituted by halogen, C1 -C4 alkyl, C1 -C4 alkoxy, nitro or hydroxyl; or one of R1 and R2 denotes H and the other represents naphthyl; benzyl; α,α-dimethylbenzyl; cyclohexyl; biphenyl; thienyl; or adamantyl; with the proviso that if one of the groups R1 and R2 denotes H, the other is different from H or methyl;
R3 represents H or C1 -C4 lower alkyl; and
R4 represents:
a group: ##STR271## in which A1 denotes linear or branched C2 -C5 alkyl, and R6 and R7, taken independently, represent H, C1 -C4 alkyl or C3 -C6 cycloalkyl, or alternatively R6 and R7, taken with the nitrogen atom to which they are bonded, form a pharmaceutically-acceptable 5-membered or 6-membered heterocycle containing one or two nitrogen atoms as ring members or a nitrogen atom and an oxygen atom as ring members;
a group: ##STR272## in which A2 denotes a group (CH2)m, where m=0, 1, 2 or 3, which is bonded to the pyridine ring in the 2-, 3- or 4-position;
a group: ##STR273## in which A2 is as indicated above; or a group: ##STR274## in which R6 denotes C1 -C4 alkyl; or alternatively the substituent ##STR275## represents a group: ##STR276## in which R8 is as indicated above; or an addition salt thereof with a pharmaceutically acceptable mineral or organic acid.
Description

This application is a continuation of application Ser. No. 167,291, filed Mar. 11, 1988 now abandoned.

The present invention relates to novel thiazole derivatives, a process for their preparation and their application in therapy.

According to a first aspect, the invention relates, by way of novel products, to thiazole derivatives corresponding to the general formula: ##STR3## in which: R1 and R2 each independently represent hydrogen; a C1 -C4 alkyl group; a phenyl group or a phenyl group monosubstituted or polysubstituted by a halogen atom, preferably chlorine or fluorine, by a C1 -C4 alkyl group, preferably the methyl group, or by a C1 -C4 alkoxy, nitro or hydroxyl group; or one of the groups R1 and R2 denotes hydrogen and the other represents a naphthyl group; a benzyl group; an α,α-dimethyl-benzyl group; a cyclohexyl group; a biphenyl group; a thienyl group or an adamantyl group; or alternatively R1 and R2, taken together, represent a group: ##STR4## in which the phenyl group is bonded to the 4-position of the thiazole and the group (CH2)m to 5-position, and in which m represents an integer equal to 2 or 3 and R5 denotes hydrogen or a nitro group occupying one of the free positions on the ring, with the proviso that if one of the groups R1 or R2 denotes hydrogen, the other is different from H or methyl;

R3 represents hydrogen or a C1 -C4 lower alkyl group; and

R4 represents:

a group: ##STR5## in which A1 denotes a linear or branched C2 -C5 alkyl group and R6 and R7, taken independently, represents hydrogen, a C1 -C4 alkyl group or C3 -C6 cycloalkyl group, or alternatively R6 and R7, taken with the nitrogen atom to which they are bonded, form a 5-membered or 6-membered heterocycle optionally containing a second heteroatom, and especially the pyrrolidine, piperidine, morpholine and N-alkylpiperazine rings;

a group: ##STR6## in which A2 denotes a group (CH2)m, where m=0, 1, 2 or 3, which substitutes the pyridine ring in the 2-, 3- or 4-position;

a group: ##STR7## in which A2 is as indicated above; or a group: ##STR8## in which R8 denotes a C1 -C4 alkyl group; or alternatively the substituent ##STR9## represents a group: ##STR10## in which R8 is as indicated above, and also their addition salts with mineral or organic acids.

If the substituent R6 contains an asymmetric carbon atom, the compounds (I) exist in the form of 2 optical isomers. These optical isomers form an integral part of the invention.

According to a second aspect, the invention relates to a process for the preparation of the compounds of formula (I).

The process for the preparation of the thiazole derivatives as hereinabove defined comprises the steps of heating in an acid medium of pH 1 to 6, a substituted thiourea of the formula: ##STR11## in which R3 has the meaning indicated above and R'4 has the same meanings as R4 except in cases where R4 contains a primary or secondary amine, when R'4 denotes the group corresponding to R4 in which a hydrogen belonging to the said amine group has been replaced by a protective group which is resistant to hydrolysis in an alkaline medium, with an alpha-brominated carbonyl derivative of the formula: ##STR12## or with the corresponding bromine derivative in which the carbonyl group is protected in the form of an acetal, to give the compounds (I), and of converting the compound I to a salt, if desired, by a known process.

The substituted thiourea used in the invention process can be obtained by conventional processes, for example by action of a benzyl isothiocyanate or a pivaloylisothiocyanate on a primary amine 1.

If R3 is hydrogen, this process can be represented by the following reaction scheme: ##STR13##

Reaction of benzoyl isothiocyanate with the primary amine 1 gives the substituted benzoylthiourea 2.

In practice, the benzoyl isothiocyanate is formed in situ by reacting benzoyl chloride with potassium thiocyanate in a solvent such as anhydrous acetone.

A solution of the amine derivative 1 in a suitable solvent, especially methylene chloride, is added to the resulting solution of benzoyl isothiocyanate and the mixture is heated at a temperature between 50 C. and 100 C. for 1/2 to 3 hours.

After removal of the solvents, the reaction mixture is taken up in water and the product 2 is isolated in the usual way, either by solvent extraction and purification, or by chromatography, or by direct crystallization.

The product (I) is obtained in 2 steps from the benzoylthiourea.

First of all, the benzoyl group is removed by heating the compound 2 with a dilute aqueous solution of sodium hydroxide. The reaction mixture is acidified by the addition of an acid, for example concentrated hydrochloric acid up to a pH between 1 and 6, after which a solution of the bromine derivative 3 is a water-miscible solvent, preferably an alcohol, is added.

The mixture is heated for a few hours at a temperature between 70 and 100 C.

After evaporation of the solvents, the reaction mixture is taken up in a solution of sodium bicarbonate or carbonate and the product (I) is isolated by extraction with a solvent such as methylene chloride.

After purification by the usual methods, the compound (I) is converted to a salt, if desired, by reaction with an acid in accordance with a known process.

In this process, if the bromine derivative 3 is not very stable or not readily available, it can be replaced with the corresponding dimethylacetal.

Finally, if R4 contains a primary or secondary amine group, it has to be blocked in order to avoid a side-reaction with the benzoyl chloride. It is possible to use a protective group which is resistant to hydrolysis in an alkaline medium, such as for example a tert. butoxycarbonyl group(Boc).

The corresponding benzoylthiourea 2 is obtained from the amine R4 NH2 protected in this way. Reaction with dilute sodium hydroxide removes the benzyl group and direct reaction with the bromine derivative 3 at an acid pH causes the formation of the thiazole ring and the removal of the group Boc, leading to the compounds (I) in which R4 contains a primary or secondary amine group.

The starting materials 1 and 3 are known compounds or can be prepared by known processes. Processes for obtaining compounds 3 are notably disclosed by HOUBEN WEYL "Methoden der Organischen Chemie" 4th edition, vol. 4/5 p. 171-188-Georg Thieme Verlag.

In the particular case where R4 represents a group: ##STR14## in which at least one of the substituents R6 and R7 is hydrogen, the protected amine derivatives 1 can be prepared from the aminonitrile R7 NH-A'1 -CN. When treated with the anhydride (Boc)2 O, this gives the aminonitrile ##STR15## which, on reduction, leads to the corresponding primary amine ##STR16## in which A'1 represents A1 minus a methylene group.

In all cases, the particularly if the substituent R3 is other than hydrogen, the compounds (I) can be prepared from pivaloyl isothiocyanate according to the scheme: ##STR17##

Reaction of pivaloyl isothiocyanate with the amine 4 gives the pivaloylthiourea 5.

In practice, the pivaloyl isothiocyanate is formed in situ by reacting pivaloyl chloride with an alkali metal thiocyanate in an anhydrous solvent, such as acetone, and at a moderate temperature (0 to 10 C.). The amine 4 is then added and the mixture is left to react for a few hours at the same temperature.

The compound 5 is deacylated by hydrolysis under the action of heat in a strong acid medium, giving the thiourea 6.

This is converted to the compound (I) by reaction with a bromine derivative 3, as indicated previously.

The non-limiting examples which follow will provide a clearer understanding of the invention.

EXAMPLE 1 2-[(2-Diethylaminoethyl)amino]-5-phenylthiazole dihydrochloride (SR 44318 A)

A) N-Benzoyl-N'-(diethylaminoethyl)thiourea

A solution of 70 ml of benzoyl chloride in 100 ml of anhydrous acetone is added dropwise, at room temperature, to a suspension of 51 g of potassium thiocyanate in 300 ml of anhydrous acetone. When the addition is complete, the reaction mixture is refluxed for 5 minutes. A solution of 85 ml of 2-diethylaminoethylamine in 100 ml of methylene chloride is added slowly to the resulting hot solution, with vigorous stirring, so as to keep the mixture under reflux. When the addition is complete, the mixture is stirred for 1 hour at room temperature, the solvents are then evaporated off and the residue is taken up in iced water. Extraction is carried out twice with 200 ml of methylene chloride and the solution is dried over magnesium sulfate. The solvent is evaporated off to dryness and the oily product obtained is purified by chromatography on a silica column. Impurities of low polarity are removed by elution with an 80/20 (vol/vol) methylene chloride/ethyl acetate mixture. The expected product is then obtained by elution with a 95/5 (vol/vol) methylene chloride/methanol mixture.

Weight: 78 g; m.p.: 54-56 C.

B) SR 44318 A

3.5 g of the compound prepared above are refluxed in 18 ml of a 2.5N solution of sodium hydroxide under a nitrogen atmosphere for 30 minutes. After cooling, concentrated hydrochloric acid is added until the pH is about 6. A solution of 2.48 g of alpha-bromophenylacetaldehyde in 25 ml of 95 ethanol is added and the mixture is refluxed for 1 hour under a nitrogen atmosphere.

It is evaporated in vacuo and a 10% aqueous solution of sodium carbonate is added. Extraction is carried out twice with methylene chloride and the solution is dried over magnesium sulfate. The solvent is evaporated off and the residue is chromatographed on a silica column by elution with a 95/5 (vol/vol) methylene chloride/methanol mixture, giving an oil (1.46 g).

This oil is dissolved in anhydrous ether, a solution of hydrogen chloride in anhydrous ether is added and the mixture is left to crystallize. The crystals are filtered off, washed with anhydrous ether and dried in vacuo.

M.p.: 178 C.

EXAMPLES 2 TO 108

A) The substituted thioureas collated in Table 1 below are obtained by following the procedure of Example 1-A but varying the amine compounds used.

              TABLE 1______________________________________ ##STR18##R4              Physical constant______________________________________ ##STR19##           M.p. = 119-120 C. ##STR20##           Oil, TLC: Rf = 0.51 CH2 Cl2 /MeOH 90/10                vol/vol ##STR21##           M.p. = 67-69 C. ##STR22##           Oil ##STR23##           M.p. = 98-99 C. ##STR24##           M.p. = 70-71 C. ##STR25##           M.p. = 48-49  C. ##STR26##           M.p. = 93-94 C. ##STR27##           Oil ##STR28##           M.p. = 65-67 C. ##STR29##           M.p. = 55-57 C. ##STR30##           Oil ##STR31##           M.p. = 57-58 C. ##STR32##           M.p. = 73-75 C. ##STR33##           Oil ##STR34##           M.p. = 72-74  C. ##STR35##           M.p. = 74-75 C. ##STR36##           M.p. = 31-35 C. ##STR37##           Oil ##STR38##           M.p. = 45-48 C. ##STR39##           M.p. = 152-153 C. ##STR40##           M.p. = 98-100 C. ##STR41##           M.p. = 158-159 C. ##STR42##           M.p. = 146-147 C. ##STR43##           M.p. = 118-119 C. ##STR44##           M.p. =  142-143 C. ##STR45##           M.p. = 81-82 C. ##STR46##           M.p. = 118-120 C.______________________________________

B) The products of formula (I) collated in Table 2 below are obtained by following the procedure of Example 1-B, starting from these different thioureas and varying the oxohalogen derivative reacted therewith.

                                  TABLE 2__________________________________________________________________________ ##STR47##Ex.   SR                                     Salt M.p. C.no.   code no.   R1          R2     R4        (solvent)__________________________________________________________________________ 2 44244 A   H           ##STR48##                       ##STR49##     Dihydrochloride 220-221                                     (iPrOH/Et2 O) 3 44284 A   "      "                       ##STR50##     Dihydrochloride 216-217                                     (iPrOH) 4 44285 A    ##STR51##          H                       ##STR52##     Dihydrochloride 264-265                                     (iPrOH/EtOH 95) 5 44286 A   H           ##STR53##                       ##STR54##     Succinate 110-111 (iPrOH/iPr.sub                                     .2 O) 6 44345 A   "      "                       ##STR55##     Dihydrochloride 181-182                                     (Et2 O) 7 44346 A    ##STR56##          H                       ##STR57##     Dihydrochloride 0.5H2 O                                     143-144 (acetone) 8 44347 A   H           ##STR58##                       ##STR59##     Dihydrochloride 199-200 (cyclo-                                     exane, Et2 O) 9 44372 A   "      "                       ##STR60##     Dihydrochloride 1H2 O                                     147-148 (acetone, Et2 O)10 44373 A    ##STR61##          CH3                       ##STR62##     Dihydrochloride 0.5H2 O                                     184-5 (acetone, Et2 O)11 44374 A   H           ##STR63##  "              Dimaleate 109-111 (iPrOH,                                     Et2 O)12 44421 A   H           ##STR64##                       ##STR65##     Dihydrochloride 224-226 (iPrOH,                                     Et2 O)13 44422 A   H      CH3                       ##STR66##     Dihydrochloride 162-163 (iPrOH,                                     Et2 O)14 44424 A   H           ##STR67##                       ##STR68##     Dihydrochloride 216-217 (iPrOH,                                     Et2 O)15 44434 A   CH3           ##STR69##                       ##STR70##     Dihydrochloride 0.5H2 O                                     148-149 (iPrOH, Et2 O)16 44435 A    ##STR71##           ##STR72##                       ##STR73##     Dihydrochloride 0.5H2 O                                     167-168 (iPrOH, iPr2 O)17 44436 A   "      CH3                       ##STR74##     Dihydrochloride 0.5H2 O                                     154-155 (Et2 O)18 44437 A    ##STR75##           ##STR76##                       ##STR77##     Dihydrochloride 193-194                                     (Et2 O)19 44438 A   "      H                       ##STR78##     Dihydrochloride 0.5H2 O                                     190-195 (dec) (Et2 O)20 44451 A   H           ##STR79##                       ##STR80##     Dihydrochloride 141-142                                     (Et2 O, PrOH)21 44465 A   H           ##STR81##                       ##STR82##     Dihydrochloride 184-186 (dec)                                     (iPrOH, Et2 O)22 44466 A    ##STR83##          CH3                       ##STR84##     Dihydrochloride 204-207 (dec)                                     (iPrOH)23 44467 A    ##STR85##          CH3                       ##STR86##     Dihydrochloride 235-236 (dec)                                     (iPrOH, iPr2 O)24 44468 A   H           ##STR87##                       ##STR88##     Dihydrochloride 196-199 (iPrOH,                                     iPr2 O)25 44469 A   H           ##STR89##                       ##STR90##     Dihydrochloride 195-190 (dec)                                     (iPrOH, Et2 O)26 44488 A    ##STR91##          CH3                       ##STR92##     Dihydrochloride 178-180                                     (Et2 O)27 44489 A   "      "                       ##STR93##     Dihydrochloride 1H2 O                                     130-135 (iPrOH, iPr2 O)28 44490 A   "      H                       ##STR94##     Dihydrochloride 250 (dec)                                     (Et2 O)29 44491 A   "      H                       ##STR95##     Dihydrochloride 1H2 O 93                                     (Et2 O)30 44492 A   "      H                       ##STR96##     Dihydrochloride 147 (acetone,                                     Et2 O)31 44493 A   H           ##STR97##                       ##STR98##     Dihydrochloride 1H2 O 141                                     (iPrOH, iPr2 O, H2                                     O)32 44494 A   H           ##STR99##                       ##STR100##    Dihydrochloride 1H2 O 114                                     (iPrOH, Et2 O)33 44515 A    ##STR101##           ##STR102##                       ##STR103##    Dihydrochloride 1H2 O                                     88-89 (Et2 O)34 44516 A   H           ##STR104##                       ##STR105##    Dihydrochloride 1H2 O                                     91-93 (Et2 O)35 44573 A   H           ##STR106##                       ##STR107##    Dihydrochloride 96 C.                                     (Et2 O)36 44574 A   H           ##STR108##                       ##STR109##    Dihydrochloride 155 C.                                     (Et2 O/iPrOH)37 44575 A   H           ##STR110##                       ##STR111##    Dihydrochloride 182 C.                                     (EtOH 95/iPrOH)38 44576 A   H           ##STR112##                       ##STR113##    Dihydrochloride 150-155                                     (Et2 O)39 44749 A   H           ##STR114##                       ##STR115##    Dihydrochloride 194-196                                     C. (Et2 O)40 44750 A   H      "                       ##STR116##    Fumarate 121-3 C.                                     (Et2 O)41 44768 A   H           ##STR117##                       ##STR118##    Fumarate 182-4 C.                                     (Et2 O)42 44769 A   CH3           ##STR119##                       ##STR120##    Dihydrochloride 191 C.                                     (Et2 O)43 44770 A   H           ##STR121## "              Dihydrochloride (1H2 O)                                     168 C. (Et2 O)44 44786 A   H           ##STR122##                       ##STR123##    Difumarate 138-140 C.                                     (Et2 O)45 44791 A   H           ##STR124##                       ##STR125##    Dihydrochloride (0.5H2 O)                                     175-6 C. (Et2 O)46 44814 A   H           ##STR126##                       ##STR127##    Difumarate 140-4 C.                                     (Et2 O)47 44832 A   H           ##STR128##                       ##STR129##    Dihydrochloride (0.5H2 O)                                     165 C. (Et2 O)48 44862 A   H           ##STR130##                       ##STR131##    Trihydrochloride (1H2 O)                                     249-251 C. (Et2                                     O)49 44887 A   H           ##STR132##                       ##STR133##    Dihydrochloride (1.5H2 O)                                     78-82 C. (Et2 O)50 44907 A   H      "                       ##STR134##    Difumarate (0.5H2 O)                                     173-4 C. (Et2 O)51 44908 A   H      "                       ##STR135##    Dihydrochloride 114-6                                     C. (Et2 O)52 44914 A   H           ##STR136##                       ##STR137##    Dihydrochloride 180-5                                     C. (Et2 O)53 44915 A   H           ##STR138##                       ##STR139##    Trihydrochloride  145-150.degree                                     . C. (Et2 O/iPrOH)54 44916 A   H           ##STR140##                       ##STR141##    Dihydrochloride 165-7                                     C. (iPrOH/Et2 O)55 44963 A    ##STR142##          C2 H5                       ##STR143##    Dihydrochloride (1H2 O)                                     155-6 C. (acetone)56 44964 A   H           ##STR144##                       ##STR145##    Difumarate 147-8 C.                                     (Et2 O)57 44965 A   H      "                       ##STR146##    Fumarate (1H2 O)                                     226-8 C. (Et2 O)58 44967 A    ##STR147##          H                       ##STR148##    Dihydrochloride 82 C.                                     (Et2 O)59 45001 A   H           ##STR149##                       ##STR150##    Fumarate 123 C.                                     (Et2 O)60 45015 A    ##STR151##           ##STR152## "              Dihydrochloride (0.5H2 O)                                     210 C. (Et2 O)61 45016 A    ##STR153##           ##STR154## "              Dihydrochloride (0.5H2 O)                                     207-8 C. (Et2 O)62 45018 A   H           ##STR155## "              Dihydrochloride (0.5H2 O)                                     165-7 C. (Et2 O)63 45023 A   H           ##STR156## "              Dihydrochloride 238-240                                     C. (Et2 O)64 45030 A   H           ##STR157## (CH2)3 NHCH3                                     Difumarate 138-140 C.65 45035 A   H           ##STR158##                       ##STR159##    Dihydrochloride (0.5H2 O)                                     222-5 C. (Et2 O)66 45038 A   H           ##STR160## "              Trihemifumarate 129-130                                     C. (Et2 O)67 45043 A    ##STR161##          H           "              Trihemifumarate 102-3                                     C. (Et2 O)68 45079 A   H           ##STR162## "              Dihydrochloride (1H2 O)                                     130-2 C. (Et2 O)69 45080 A   H           ##STR163## "              Dihydrochloride (0.5H2 O)                                     228 C. (Et2 O)70 45088 A    ##STR164##          C2 H5                      "              Trihemifumarate 125-6                                     C. (Et2 O)71 45107 A   H           ##STR165##                       ##STR166##    Fumarate 114 C.                                     (Et2 O)72 45108 A   H           ##STR167##                       ##STR168##    Monohydrochloride (1H2 O)                                     202 C. (Et2 O)73 45125 A   H      "                       ##STR169##    Difumarate 132-3 C.                                     (Et2 O)74 45137 A    ##STR170##          H                       ##STR171##    Monohydrochloride 183                                     C. (Et.sub. 2 O)75 45154 A   H           ##STR172##                       ##STR173##    Difumarate 126-7 C.                                     (Et2 O)76 45190 A   H           ##STR174##                       ##STR175##    Difumarate (0.5H2 O)                                     116-8 C. (Et2 O)77 44813 A   H           ##STR176##                       ##STR177##    Dihydrochloride 246-8                                     C. (Et2 O)78 44833 A   H           ##STR178## "              Dihydrochloride 125-6                                     C. (Et2 O)79 44839 A   H           ##STR179##                       ##STR180##    Dihydrochloride (0.5H2 O)                                     245 C. (Et2 O)80 44840 A   H           ##STR181##                       ##STR182##    Dihydrochloride (1H2 O)                                     219-220 C. (Et2                                     O)81 44856 A   H           ##STR183##                       ##STR184##    Dihydrochloride 225-6                                     C. (Et2 O)82 44863 A   H           ##STR185##                       ##STR186##    Dihydrochloride (2H2 O)                                     111-2 C. (Et2 O)83 44864 A   H           ##STR187##                       ##STR188##    Dihydrochloride (2H2 O)                                     237-9 C. (Et2 O)84 44902 A    ##STR189##           ##STR190##                       ##STR191##    Dihydrochloride (0.5H2 O)                                     183 C. (Et2 O)85 44903 A   H           ##STR192##                       ##STR193##    Dihydrochloride 200-2                                     C. (Et2 O)86 44904 A    ##STR194##           ##STR195##                       ##STR196##    Dihydrochloride (1H2 O)                                     133-5 C. (Et2 O)87 44905 A   H           ##STR197##                       ##STR198##    Dihydrochloride (1.5H2 O)                                     122 C.  (Et2 O)88 44906 A    ##STR199##           ##STR200##                       ##STR201##    Dihydrochloride (1H2 O)                                     173 C. (Et2 O)89 44913 A   H           ##STR202##                       ##STR203##    Monohydrochloride 171                                     C. (Et2 O)90 44911 A    ##STR204##           ##STR205##                       ##STR206##    Monohydrochloride 221                                     C. (Et2 O)91 44912 A   "      "                       ##STR207##    Monohydrochloride 150                                     C. (Et2 O)92 44966 A    ##STR208##          H                       ##STR209##    Fumarate 148 C.                                     (Et2 O)93 44968 A   "      H                       ##STR210##    Fumarate 147-8 C.                                     (Et2 O)94 44998 A   "      H                       ##STR211##    Dihydrochloride (1H2 O)                                     211 C. (Et2 O)95 45002 A   "      H                       ##STR212##    Dihydrochloride (2H2 O)                                     94 C. (Et2 O)96 45106 A   H           ##STR213##                       ##STR214##    Dihydrochloride 137 C.                                     (Et2 O)97 45124 A    ##STR215##          C2 H5                       ##STR216##    Dihydrochloride 213-6                                     C. (Et2 O)98 45122 A   H           ##STR217##                       ##STR218##    Monohydrochloride >250                                     C. (Et2 O)99 45123 A   H           ##STR219## "              Monohydrochloride 184                                     C. (Et2 O)100   45169 A   H           ##STR220##                       ##STR221##    Dihydrochloride 201-4                                     C. (iPrOH/EtOH)101   45185 A    ##STR222##          H                       ##STR223##    Base (1H2 O) 163                                     C. (Et2 O)102   45221 A   H           ##STR224##                       ##STR225##    Dihydrochloride 207-9                                     C. (iPrOH)103   45253 A   H           ##STR226##                       ##STR227##    Monohydrochloride 160                                     C. (Et2 O)104   45240 A   H      "                       ##STR228##    Dihydrochloride 191-2                                     C. (Et2 O)105   45239 A   H           ##STR229##                       ##STR230##    Dihydrochloride 227-9                                     C. (Et2 O)106   45255 A   H           ##STR231##                       ##STR232##    Monohydrochloride (0.5H2                                     O) 200-1 C. (Et2                                     O)107   45264 A   H           ##STR233##                       ##STR234##    Dihydrochloride 221-3                                     C. (iPrOH/Et2 O)108   45258 A   H      "                       ##STR235##    Oxalate 170-172 C.                                     (acetone)__________________________________________________________________________ iPrOH = isopropanol; PrOH = propanol; EtOH 95 = 95 ethanol; Et2 O = anhydrous ethyl ether; iPr2 O = isopropyl ether
EXAMPLE 109 2-[(3-Aminopropyl)amino]-5-methyl-4-phenylthiazole dihydrochloride (SR 44514 A)

A) 3-N-Boc-aminopropionitrile

56 ml of triethylamine are added to a solution of 26 g of 3-aminopropionitrile fumarate in 100 ml of water and the mixture is then heated to 50 C. A solution of 46 g of dicarbonic acid bis-tert.-butyl ester (Boc2 O) in 100 ml of dioxane is then added with vigorous stirring.

After evaporation of the solvent, the residue is taken up with methylene chloride. The organic solution is washed with a 5% aqueous solution of sodium carbonate is dried over magnesium sulfate and the solvent is evaporated off. The residue (38.8 g) crystallizes.

B) 3-N-Boc-aminopropylamine

20 g of the above product are dissolved in a mixture of 400 ml of water, 40 ml of aqueous ammonia and 50 ml of ethanol. Raney nickel is added and the mixture is hydrogenated at ordinary temperature and pressure.

After the catalyst has been filtered off, the solvents are evaporated off in vacuo. The residue is taken up in an aqueous solution of sodium chloride and extracted with ethyl acetate. The solution is dried over magnesium sulfate and the solvent is evaporated off to give 12.6 g of the expected product.

C) N-Benzoyl-N'-(3-N-Boc-aminopropyl)thiourea

A solution of 6.38 ml of benzoyl chloride in 20 ml of anhydrous acetone is added dropwise to a suspension of 7.05 g of potassium thiocyanate in 50 ml of anhydrous acetone and the mixture is then refluxed for 5 minutes.

A solution of 12.6 g of 3-N-Boc-aminopropylamine in 20 ml of methylene chloride is added slowly to the hot solution, with vigorous stirring.

When the addition is complete, the mixture is stirred for 1 hour, the solvents are then evaporated off and the residue is taken up in iced water. Extraction is carried out with ethyl acetate and the solution is dried over magnesium sulfate. The solvent is evaporated off and the residue is taken up in 100 ml of cold anhydrous ether.

The crystals formed are filtered off, washed with cold ether and dried in an oven at 70 C.

Weight: 8.3 g; m.p.: 104-105 C.

D) SR 44514 A

3.37 g of the product obtained above are refluxed in 14 ml of a 2.5N solution of sodium hydroxide for 15 minutes.

After cooling, concentrated hydrochloric acid is added until the pH is 1. A solution of 2.13 g of 2-bromopropiophenone in 20 ml of ethanol is added and the mixture is refluxed for 1 hour under a nitrogen atmosphere.

The mixture is treated as indicated in Example 1-B to give an oil.

The dihydrochloride is formed in solution in methanol by the addition of a solution of hydrogen chloride in ether.

M.p.: 100-110 C.

EXAMPLES 110 AND 111

The following are obtained in the same way, starting from the substituted thiourea prepared in Example 109-C and following the procedure of Example 109-D but varying the bromine derivative used:

EXAMPLE 110 2-[(3-Aminopropyl)amino]-4-(4-fluorophenyl)thiazole (SR 44886 A) isolated in the form of the fumarate (0.5H2 O). M.p.: 162-164 C. EXAMPLE 111

2-[(3-Aminopropyl)amino]-4-(2,4,6-trimethylphenyl)thiazole (SR 44949 A) isolated in the form of the fumarate. M.p.: 163-164 C.

EXAMPLE 112 2-[N-Methyl-N-(pyridyl-3-methyl)amino]-4-(2,4,6-trimethylphenyl)thiazole oxalate (SR 45206 a) ##STR236##

A) N-Methyl-N-(pyridyl-3-methyl)thiourea

24.6 ml of pivaloyl chloride are added dropwise, with thorough stirring, to a suspension of 16.2 g of sodium thiocyanate in 90 ml of anhydrous acetone, cooled to +4 C. The mixture is stirred for 3 hours at +4 C. and 25 g of 3-methylaminomethylpyridine are then added dropwise so as to keep the temperature between 0 and +4 C. The temperature is allowed to rise to 20 C. and the mixture is stirred for 15 hours at this temperature. It is evaporated in vacuo and the residue is taken up in 100 ml of concentrated hydrochloric acid. The solution is heated at 95 C. for 1 hour. After cooling, extraction is carried out twice with methylene chloride and the aqueous phase is then rendered alkaline with a concentrated solution of sodium hydroxide. Extraction is carried out 4 times with 200 ml of methylene chloride. The organic extracts are combined and dried over magnesium sulfate. The solvent is evaporated off and the residue crystallizes. The crystals are triturated with 100 ml of ether and filtered off. After drying, 26.7 g of the expected compound are obtained. M.p.: 119-120 C.

B) SR 45206 A

A mixture of 3.6 g of the thiourea prepared above, 6 g of 2,4,6-trimethylphenacyl bromide, 20 ml of water, 50 ml of ethanol and 2 ml of concentrated hydrochloric acid is refluxed for 4 hours.

After evaporation in vacuo, the residue is taken up in 150 ml of methylene chloride and extraction is carried out with 150 ml of a 1N aqueous solution of hydrochloric acid. The organic phase is re-extracted 3 times with 100 ml of 1N hydrochloric acid alkaline with sodium hydroxide solution and extracted 4 times with 150 ml of methylene chloride. The organic extracts are combined and dried over magnesium sulfate and the solvent is evaporated off. The oily residue is chromatographed on a silica column (100 g). Elution with a 97/3 vol/vol methylene chloride/methanol mixture gives 4.5 g of oily product.

OXALATE

The 4.5 g of the above product are dissolved in 30 ml of acetone and a solution of 1.4 g of oxalic acid in 40 ml of acetone is added.

The pale yellow crystals formed are filtered off, washed with a small volume of acetone and dried.

4.3 g of the expected product are obtained. M.p.: 160-161 C.

EXAMPLES 113 TO 117

The substituted thioureas collated in Table 3 are obtained in the same way by following the procedure of Example 112-A.

              TABLE 3______________________________________ ##STR237## ##STR238##            Melting point______________________________________ ##STR239##           M.p.: 174-5 C. ##STR240##           M.p.: 40-4 C. ##STR241##           M.p.: 141-3 C.______________________________________

B) The compounds I in Table 4 are obtained from these different thioureas by following the procedure of Example 112-B.

                                  TABLE 4__________________________________________________________________________ no.Ex.    no.SR code    R1          R2                      ##STR242##   C.Melting pointSalt                                  isolated__________________________________________________________________________113   45215 A   H          ##STR243##                      ##STR244##  Monohydrochloride (1H2 O)                                  145-7 C. (Et2 O)114   45216 A    ##STR245##         H           "            Monohydrochloride 210-1 C.                                  (Et2 O)115   45223 A   H          ##STR246## "            Dihydrochloride 231-2 C.                                  (Et2 O)116   45191 A   H          ##STR247##                      ##STR248##  Oxalate 44-5 C.117   45257 A   H     "                      ##STR249##  Dihydrochloride 224-6 C.                                  (iPrOH/iPr2 O)__________________________________________________________________________
EXAMPLE 118 2-(2-Morpholinoethylamino)-4,5-dihydronaphtho[1,2-d]thiazole dihydrochloride (SR 44273 A)

3.66 g of N-benzoyl-N'-(morpholinoethyl)thiourea are refluxed in 17.5 ml of a 2.5N solution of sodium hydroxide under a nitrogen atmosphere for 15 minutes. After cooling, concentrated hydrochloric acid is added until the pH is 7. A solution of 3 g of 2-bromo-1,2,3,4-tetrahydronaphthalen-1-one in 20 ml of ethanol is added and the mixture is refluxed for 1 hour. After evaporation of the solvent, the residue is neutralized by the addition of sodium bicarbonate and extraction is carried out twice with methylene chloride. The organic phase is dried over magnesium sulfate and chromatographed on a silica column by elution with a methylene chloride/methanol mixture (95/5 vol/vol).

After evaporation of the solvents, the oily residue is taken up in either and the hydrochloride is precipitated in ether. It is filtered off and recrystallized from an isopropanol/95 ethanol mixture.

M.p.: 255-257 C.

EXAMPLES 119 TO 124

The products of formula (I) collated in Table 5 are obtained by following the procedure of Example 118 but varying the bromine derivatives and/or the benzoylthioureas.

              TABLE 5______________________________________ ##STR250## no.Ex. no.SR code          m     n                     ##STR251##                               (solvent)M.p. C.Salt______________________________________119  44317 A  3     2                     ##STR252##                              Dihydrochloride 217 (iPrOH/EtOH 95)120  44323 A  3     2                     ##STR253##                              Dihydrochloride 170 (iPrOH/Et2                              O)121  44326 A  3     3    "         Dihydrochloride                              0.5H2 O 192                              (iPrOH/iPr2 O)122  44327 A  3     3                     ##STR254##                              Dihydrochloride 1H2 O 198                              (Et2 O)123  44392 A  3     3                     ##STR255##                              Dihydrochloride 0.5H.sub. 2 O 245 dec                              (Et2 O)124  44393 A  2     2                     ##STR256##                              Dihydrochloride 0.5H2 O 181                              (Et2 O/PrOH)______________________________________
EXAMPLE 125 2-[(2-Diethylaminoethyl)amino]-9-nitro-5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-d]thiazole dihydrochloride (SR 44411 A)

The procedure of Example 118 is followed using N-benzoyl-N'-(3-diethylaminopropyl)thiourea and 2-bromo-8-nitrobenzocycloheptan-1-one as the starting materials.

The expected product is obtained in the same way in the form of the dihydrochloride.

M.p.: 192-195 C. (isopropanol/95 ethanol).

The products according to the invention were studied for their pharmacological properties and in particular for their affinity for muscarinic cholinergic receptors.

The study was carried out by means of in vitro biochemical tests and also by means of pharmacological tests performed on animals.

IN VITRO BIOCHEMICAL STUDY

There are two subclasses of muscarinic cholinergic receptors in mammals: the M1 and M2 receptors.

The M1 -type receptors are concentrated in certain regions of the brain, such as the hippocampus, the cerebral cortex and the striatum, and also in the sympathetic ganglia. These binding sites can be selectively labeled with tritiated pirenzepine (3 H-PZ). The M2 -type receptors predominate in the heart and the ileum and can be labeled with tritiated N-methylscopolamine (3 H-NMS). The selectivity of the products of the invention with respect to the M1 and M2 sites was determined by studying their in vitro interaction with 3 H-PZ and 3 H-NMS firmly bound with a high affinity to rat hippocampus membranes and smooth guinea-pig ileum muscle, respectively.

Methodologies

A) Testing for affinity for the M1 -type muscarinic cholinergic receptor

The interaction of the molecules with the M1 -type muscarinic receptors was studied by in vitro measurement, on a rat hippocampus homogenate, of the displacement of tritiated pirenzepine from its specific binding sites. Aliquots (10 μl) of a 5% (w/v) rate hippocampus homogenate in an Na2 HPO4 buffer (50 mM, pH 7.40) are incubated for 2 hours at 4 C. in the presence of 3 H-PZ (76 Ci/mmol; final concentration 1 nM) and increasing concentrations of the test product. The final volume is 2 ml. The reaction is stopped by centrifugation for 10 minutes at 50,000g. After decantation and washing of the residues, the bound radioactvity is counted by liquid scintillation. The non-specific binding is determined in the presence of 10 μM atropine sulfate. The 50% inhibitory concentration (IC50) is determined graphically. (Ref.: J. D. Watson, W. R. Roeskoe and H. I. Yamamura, Life Sci., 1982, 31, 2019-2029.)

B) Testing for affinity for the M2 -type muscarinic cholinergic receptor

The interaction with the M2 -type muscarinic receptors was studied by in vitro measurement, on a smooth guinea-pig ileum muscle homogenate, of the displacement of tritiated N-methylscopolamine from its specific binding sites. Aliquots (50 μl) of a 0.625% (w/v) smooth guinea-pig ileum muscle homogenate in 20 mM HEPES buffer--2-(2-hydroxy-4-ethylpiperazin-1-yl)ethanesulfonic acid containing NaCl (100 mM) and MgCl2 (10 mM) (final pH: 7.5)--are incubated for 20 minutes at 30 C. in the presence of 3 H-NMS (85 Ci/mmol; final concentration 0.3 nM) and increasing concentrations of the test products. The final volume is 1 ml. The reaction is stopped by centrifugation for 5 minutes at 15,000g. The non-specific binding is determined in the presence of 10 mM atropine sulfate. (Ref.: R. Hammer et al., Nature, 1980, 283, 90-92; E. C. Hulme et al., Mol. Pharmacol., 1978, 14, 737-750.)

Results

Table 6 indicates the affinities of the products of the invention for the M1 and M2 receptors. The results are expressed as 50 percent inhibitory concentrations (IC50), i.e. the concentration (in μM) which induces the displacement of 50% of the tritiated ligand bound to the membrane receptors. The IC50 for 3 H-PZ displacement represents the affinity for the M1 receptor; the IC50 for 3 H-NMS displacement represents the affinity for the M2 receptor.

Also, the next column of the table indicates the ratio R of the IC50 values for the M1 and M2 receptors, which expresses the selectivity of the products with respect to one of the receptor types.

By way of comparison, Table 6 indicates the results obtained with 3 reference products.

              TABLE 6______________________________________ no.Product     IC50 μM3 H-PZ(M1)                IC50 μM3 H-NMS(M2)                           ##STR257##______________________________________SR 44284 A    8          40         5SR 44286 A    6          100        16SR 44318 A    3.4        38         11SR 44323 A    1.7        8.5        5SR 44326 A    2.2        >100       >45SR 44327 A    1.9        38         20SR 44345 A    1          70         70SR 44346 A    2          25         12.5SR 44347 A    0.35       13         37SR 44372 A    0.12       5          41SR 44373 A    0.70       15         21SR 44374 A    0.40       8          20SR 44393 A    2.7        42         15SR 44411 A    0.9        6.7        7SR 44421 A    3.6        >100       >27SR 44422 A    8.1        100        12SR 44423 A    6.4        100        15SR 44434 A    1.5        70         46SR 44435 A    0.36       3          8SR 44436 A    1.7        50         29SR 44437 A    0.43       3          7SR 44438 A    1          60         60SR 44451 A    6          80         13SR 44465 A    2.6        40         15SR 44467 A    1.5        38         25SR 44468 A    1.2        22         18SR 44469 A    2.6        60         23SR 44488 A    1.7        34         20SR 44489 A    0.3        2          6SR 44490 A    1.5        25         16SR 44491 A    0.8        8.5        10SR 44492 A    3.6        28         8SR 44493 A    1.6        45         28SR 44494 A    0.8        80         100SR 44514 A    0.5        >100       >200SR 44515 A    0.2        3.4        17SR 44516 A    3.4        75         22SR 44573 A    1.8        13         7SR 44574 A    0.2        24         120SR 44575 A    7          >100       >14SR 44749 A    1.8        26         14SR 44769 A    2          30         15SR 44770 A    0.6        26         43SR 44786 A    0.6        40         67SR 44791 A    5          40         8SR 44792 A    1.8        30         17SR 44813 A    6          >100       >17SR 44814 A    1.4        10         7SR 44832 A    2.4        >100       >42SR 44839 A    0.4        100        250SR 44840 A    0.6        >100       >167SR 44856 A    0.3        > 100      >300SR 44862 A    3          34         11SR 44864 A    0.28       >100       >360SR 44886 A    6.3        70         11SR 44904 A    6          >100       >17SR 44905 A    2.4        60         25SR 44906 A    2.4        >100       >42SR 44908 A    0.13       4          31SR 44915 A    0.4        40         100SR 44916 A    0.13       5          38SR 44963 A    0.12       6          50SR 44964 A    0.9        28         31SR 44965 A    1.2        60         50SR 44966 A    4.5        100        22SR 44967 A    1.8        40         22SR 45001 A    2.60       30         11SR 45015 A    0.3        4          13SR 45016 A    0.10       5.5        55SR 45030 A    1.60       80         50SR 45106 A    3          >100       >33Oxotremorine    0.24       0.2        1Arecoline    17         4.5        0.3Pilocarpine    2.5        7          3______________________________________

The results show that the compounds according to the invention have a strong affinity for muscarinic cholinergic receptors, with a marked specificity for the M1 -type central receptors.

IN VIVO PHARMACOLOGICAL STUDY

Pirenzepine (PZ) is a specific antagonist of the M1 central muscarinic cholinergic receptors. The intrastriatal injection of PZ into mice induces rotatory behavior. The antagonism of this behavior by the products according to the invention was studied.

The products according to the invention are administered either intrapertioneally (i.p.) or orally (p.o.) after solubilization in distilled water or suspension in a 5% solution of gum arabic. The control animals receive the pure solvent under the same conditions.

The animals used are female mice (Swiss, CD 1, Charles River, France) with a body weight of between 25 and 30 grams.

The pirenzepine is dissolved in a phosphate buffer and the pH of the solution is 6.

The test products or their solvents are administered in a volume of 0.4 ml per 20 g of body weight, either by i.p. injection or orally via an esophageal tube. Administration takes place either 15 minutes (i.p.) or 30 minutes (p.o.) before a direct injection of pirenzepine into the right striatum of the mouse at a dose of 1 μg in 1 μl of solvent, according to the method described by P. WORMS et al. in Eur. J. Pharmacol., 1986, 121, 395-401.

The number of contralateral rotations (rotations in the opposite direction to the side injected) was counted for three 2-minute periods after injection of the pirenzepine: 2nd to 4th, 8th to 10th and 13th to 15th minutes. Each treatment consists of 3 to 4 doses and 10 animals per dose. The total number of rotations and the percentage antagonism with respect to the control group are calculated for each treatment.

The 50% effective dose (ED50), i.e. the dose which causes a 50% reduction in the number of rotations induced by pirenzepine, is determined graphically for each product. The results are reported in Table 7.

Table 7 indicates, for each product tested, the 50% effective dose (ED50) in mg/kg in mice for the antagonism of the rotations induced by pirenzepine, either by i.p. administration or by oral administration.

By way of comparison, the results obtained with 3 reference products have been reported.

              TABLE 7______________________________________        Pirenzepine  Pirenzepine        antagonism   antagonismProduct no.  ED50 mg/kg i.p.                     ED50 mg/kg p.o.______________________________________SR 44244 A   8            20SR 44284 A   8            --SR 44285 A   3            --SR 44286 A   3            10SR 44318 A   1.5          3SR 44323 A   10           --SR 44326 A   3            --SR 44327 A   10           --SR 44345 A   0.5          1SR 44346 A   1            --SR 44347 A   0.03         0.20SR 44372 A   1            3SR 44373 A   0.3          1SR 44374 A   3            --SR 44392 A   3            --SR 44393 A   3            --SR 44411 A   15           --SR 44421 A   --           0.2SR 44435 A   2            --SR 44467 A   --           3SR 44493 A   --           0.3SR 44494 A   --           2SR 44514 A   3            --SR 44573 A   --           2.5SR 44749 A   --           3SR 44770 A   --           3SR 44792 A   --           3SR 44814 A   --           0.2SR 44839 A   --           0.2SR 44856 A   --           3SR 44862 A   --           3SR 44887 A   --           0.3SR 44915 A   --           3SR 44949 A   --           10SR 44964 A   --           3SR 44965 A   --           3SR 45001 A   --           3SR 45015 A   --           0.70SR 45016 A   --           2SR 45030 A   --           1Oxotremorine*        0.005        --Arecoline*   1            0.5Pilocarpine* 1            10______________________________________ *Strong induction of sideeffects (trembling, salivation, lacrimation, defecation, piloerection, hypothermia, sedation) at doses close to the active doses in these tests.

The results in Table 7 show that the compounds according to the invention are active in stimulating central cholinergic transmission and are therefore capable of being used as agonists of muscarinic receptors.

Furthermore, some of the products according to the invention displayed an antagonistic activity towards the effect of excitatory amino acids in the brain. This activity was measured in the test for the release of acetylcholine caused by N-methyl-D-aspartic acid (NMDA) on sections of rat striatum (J. Lehmann and B. Scatton, Brain Research 1982, 252, 77-89).

Finally, the acute toxicity was determined for various products according to the invention. The products were administered intrapertioneally in increases doses to groups of 10 female mice (Swiss, CD 1, Charles River, France) with a body weight of 20 g.

The mortality caused by the products studied was noted for 24 hours following administration of the product. The 50% lethal dose (LD50), i.e. the dose which causes the death of 50% of the animals, was determined for each of the products.

The results obtained are collated in Table 8 below.

              TABLE 8______________________________________Product no.   LD50 (mg/kg) i.p.______________________________________SR 44244 A    250SR 44273 A    >100SR 44284 A    450SR 44286 A    200SR 44345 A    200SR 44347 A    60SR 44372 A    75SR 44373 A    75SR 44374 A    150______________________________________

The products according to the invention therefore have a low toxicity and show no signs of toxicity for the doses at which they are active.

Consequently, the compounds (I) can be used as drugs.

The results indicated above make it possible to consider using the products according to the invention for treating degenerative syndromes associated with senescence, and especially memory disorders and senile dementia.

According to another of its aspects, the present application therefore relates to pharmaceutical compositions which contain at least one of the compounds of formula (I) or one of their salts as the active ingredient.

In the pharmaceutical compositions of the present invention for oral, sublingual, percutaneous or rectal administration, the active ingredients of formula I above can be administered to humans in single dosage forms, mixed with the conventional pharmaceutical excipients, especially for the treatment of senile dementia. The appropriate unit dosage forms include oral dosage forms, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, sublingual and buccal dosage forms, subcutaneous, intramuscular or intravenous dosage forms and rectal dosage forms.

To achieve the desired effect, the dose of active principle can vary between 20 and 500 mg per day.

Each unit dose can contain from 5 to 200 mg of active ingredient combined with a pharmaceutical excipient. This unit dose can be administered 1 to 4 times per day.

When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other appropriate substances, or else they can be treated so as to have a sustained or delayed activity and continuously release a predetermined amount of active principle.

A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

Water-dispersible granules or powders can contain the active ingredient mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, and with sweeteners or taste correctors.

For rectal administration, suppositories are used; these are prepared with binders which melt at the temperature of the rectum, for example cacao butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic salt solutions or solutions which are sterile and injectable are used; these contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.

The active principle can also be formulated as microcapsules, together with one or more excipients or additives if appropriate.

As an example of a pharmaceutical preparation, it is possible to prepare gelatin capsules containing:

______________________________________SR 44421 A             0.010  glactose                0.050  gmagnesium stearate     0.005  g______________________________________

by intimately mixing the above ingredients and pouring the mixture into hard gelatin capsules.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US4064244 *Jun 18, 1975Dec 20, 1977Sandoz Ltd.Anorexigenic agents, antimigraine agents
US4241072 *Jan 18, 1979Dec 23, 1980Merck & Co., Inc.Gastric secretion inhibitory properties
US4517196 *Aug 26, 1982May 14, 1985Basf AktiengesellschaftTricyclic thiazolyloxamic acids and their derivatives, their preparation, and therapeutic agents containing these compounds
Non-Patent Citations
Reference
1 *Chem. Abstracts, vol. 75(21), Abst. No. 129,703 J dated Nov. 22, 1971.
2Chem. Abstracts, vol. 75(21), Abst. No. 129,703-J dated Nov. 22, 1971.
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US5464847 *Jun 23, 1993Nov 7, 1995Elf SanofiModuators of corticotropin releasing factor
US6187802 *Mar 9, 1998Feb 13, 2001Knoll AktiengesellschaftSubstituted 4-arylmethylene-2-imino-2,3-dihydrothiazoles and derivatives and their pharmaceutical use
US6214853Jun 30, 1999Apr 10, 2001Synaptic Pharmaceutical CorporationSelective NPY (Y5) antagonists (bicyclics)
US6218408Jun 30, 1999Apr 17, 2001Synaptic Pharmaceutical CorporationSelective NPY (Y5) antagonists (bicyclics)
US6222040Jun 30, 1999Apr 24, 2001Synaptic Pharmaceutical CorporationSelective NPY (Y5) antagonists (tricyclics)
US6225330Jun 30, 1999May 1, 2001Synaptic Pharmaceutical CorporationFor treatment of abnormal conditions such as feeding disorders (obesity and bulimia nervosa), sexual/reproductive disorders, depression, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances
US6340683Apr 22, 1999Jan 22, 2002Synaptic Pharmaceutical CorporationSelective NPY (Y5) antagonists (triazines)
US6569856Jan 3, 2002May 27, 2003Synaptic Pharmaceutical CorporationTreatment of feeding disorders, obesity, bulimia nervosa, sexual/reproductive disorders, depression, epileptic seizure, cardiovascular disorders, sleep disturbances
US6699866Apr 12, 2002Mar 2, 2004Sepracor Inc.For therapy of addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, alzheimer's disease, obesity, emesis, psychosis, analgesia, schizophrenia, parkinson's disease, restless leg syndrome, sleeping disorders
US6989379Apr 21, 2000Jan 24, 2006H. Lundbick A/SSelective NPY (Y5) antagonists
US7087623Feb 25, 2004Aug 8, 2006Sepracor Inc.Thiazole and other heterocyclic ligands for mammalian dopamine, muscarinic and serotonin receptors and transporters, and methods of use thereof
US7189720Apr 6, 2005Mar 13, 2007H. Lundbeck A/SSelective NPY (Y5) antagonists
US7273880Jan 20, 2005Sep 25, 2007H. Lunbeck A/SSelective NPY (Y5) antagonists
US7514566Jan 11, 2007Apr 7, 2009Amgen, Inc.Thiazole compounds and methods of use
US7919504Jul 15, 2008Apr 5, 2011Amgen Inc.Thiadiazole modulators of PKB
US8084479Feb 11, 2009Dec 27, 2011Amgen Inc.Thiazole compounds and methods of use
WO2000064880A1 *Apr 21, 2000Nov 2, 2000Mahesh N DesaiSelective npy (y5) antagonists
WO2010083246A1Jan 13, 2010Jul 22, 2010Amgen Inc.Fluoroisoquinoline substituted thiazole compounds and methods of use
WO2011133733A1 *Apr 21, 2011Oct 27, 2011Merck Sharp & Dohme Corp.Inhibitors of akt activity
Classifications
U.S. Classification514/231.5, 548/190, 546/209, 548/193, 514/342, 514/370, 546/163, 548/222, 546/270.1, 514/314, 514/254.02, 544/133, 544/367, 546/270.7, 514/320
International ClassificationC07D277/84, C07D277/60, C07D277/42
Cooperative ClassificationC07D277/84, C07D277/60, C07D277/42
European ClassificationC07D277/42, C07D277/84, C07D277/60
Legal Events
DateCodeEventDescription
Oct 9, 2001FPExpired due to failure to pay maintenance fee
Effective date: 20010803
Aug 5, 2001LAPSLapse for failure to pay maintenance fees
Feb 27, 2001REMIMaintenance fee reminder mailed
Jan 31, 1997FPAYFee payment
Year of fee payment: 4
Nov 16, 1993ASAssignment
Owner name: ELF SANOFI, FRANCE
Free format text: CHANGE OF NAME;ASSIGNOR:SANOFI;REEL/FRAME:006763/0399
Effective date: 19931112